ly2605541 and Diabetes-Mellitus--Type-1

There is a clinical rationale for a basal insulin with a predictable action and low inter- and intra-individual variability coupled with an improved side effect and metabolic profile. Since insulin therapy is anabolic and its initiation is commonly associated with weight gain, an insulin preparation associated with a beneficial weight profile would represent a particularly valuable therapeutic entity. LY2605541, or PEGylated insulin Lispro, has a large hydrodynamic size while still exerting the metabolic effects of insulin. This may reduce absorption and clearance of the compound following subcutaneous administration. A number of preclinical and clinical studies have been constructed to evaluate the utility of this novel insulin. The currently available data from preclinical, phase I and phase II studies suggests LY2605541 has a non-inferior glucose-lowering efficacy compared to insulin glargine in people with type 1 and type 2 diabetes and may afford a weight-loss advantage. Pre-clinical studies indicate that LY2605541 has low mitogenic potency, exerting a preferential hepatic effect on glucose homeostasis. LY2605541 appears to cause elevated transaminases and derangement of lipid profiles. On the basis of these initial observations, LY2605541 requires further extensive clinical evaluation to fully assess its risk/benefit profile in the management in people with diabetes.

Topics: Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin Lispro; Insulin, Long-Acting; Male; Polyethylene Glycols; Risk Assessment; Treatment Outcome

The basal insulin analogue LY2605541, a PEGylated insulin lispro with prolonged duration of action, was previously shown to be associated with modest weight loss in Phase 2, randomized, open-label trials in type 2 (N=288) and type 1 (N=137) diabetes mellitus (T2DM and T1DM), compared with modest weight gain with insulin glargine. Exploratory analyses were conducted to further characterize these findings.. Pearson correlations between change in body weight and other variables were calculated. Continuous variables were analysed using a mixed linear model with repeated measurements. Proportions of subjects with weight loss were analysed using Fisher's exact test for T2DM and Nagelkerke's method for T1DM.. Weight loss was more common in LY2605541-treated patients than in patients treated with insulin glargine (T2DM: 56.9 vs. 40.2%, p=0.011; T1DM: 66.1 vs. 40.3%, p<0.001). More LY2605541-treated patients experienced ≥5% weight loss compared to patients treated with glargine (T2DM: 4.8 vs. 0%, p=0.033; T1DM: 11.9 vs. 0.8%, p<0.001). In both the T1DM and T2DM studies, weight change did not correlate with baseline body mass index (BMI), or change in HDL-cholesterol in either treatment group. No consistent correlations were found across both studies between weight change and any of the variables assessed; however, weight change was significantly correlated with hypoglycaemia rate in glargine-treated T2DM patients.. In two Phase 2 trials, improved glycaemic control with long-acting basal insulin analogue LY2605541 is associated with weight loss in previously insulin-treated patients. This weight change is independent of baseline BMI or hypoglycaemia.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome; Weight Gain; Weight Loss